DESCRIPTION: Most neural communication is chemically mediated by the secretion of excitatory and inhibitory neurotransmitters at synapses onto neighboring cells that possess the appropriate neurotransmitter receptors. The most abundant and important excitatory neurotransmitter in the vertebrate nervous system is the amino acid glutamate, and much is known about the molecular, pharmacological and physiological characteristics of the glutamate receptors. Excess activation of the glutamate receptors leads to neuronal pathology and death, a process known as excitotoxicity. There is considerable evidence that excitotoxic processes are operative in a wide variety of neurological and neurodegenerative diseases, and may constitute part of a common pathway for neural death. Therefore, defining the mechanisms responsible for excitotoxicity neuronal degeneration is an important scientific goal. The applicants (and others) have data indicating that extracellular chloride is required for excitotoxic neuronal degeneration triggered by both NMDA and non-NMDA subtypes of glutamate receptors in many neurons. There has been little effort to understand the mechanisms responsible for this mode of cell death. Recent data from this group suggests that a major path for lethal chloride entry is through the well-known ligand gated chloride channels, the iGABA and iGly receptors. These results demonstrate a surprising and seemingly paradoxical role for inhibitory transmitters in excitotoxicity. They propose here a set of pharmacological, physiological and imaging studies to examine chloride and inhibitory transmitter-dependent excitotoxic cell death. The aim of the proposed experiments are to examine if this mechanism is operative in several in vitro and in vivo model systems and to test hypotheses concerning the receptor and post-receptor mechanisms involved. Besides increasing our knowledge of mechanisms of excitotoxicity, these studies may identify novel sites of action for neuroprotective agents and new strategies that may be useful in the treatment of neurological and neruodegenerative disease.